HHS Public Access Author manuscript Author Manuscript
Curr Opin Hematol. Author manuscript; available in PMC 2017 November 01. Published in final edited form as: Curr Opin Hematol. 2016 November ; 23(6): 524–529. doi:10.1097/MOH.0000000000000282.
Allogeneic Stem Cell Transplantation for Sickle Cell Disease Tara M. Robinson* and Ephraim J. Fuchs Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
Abstract Author Manuscript
Purpose of Review—As the safety and availability of allogeneic hematopoietic stem cell transplantation (HSCT) have improved, this procedure is becoming a viable option for nonmalignant conditions such as sickle cell disease (SCD). There are very few treatment options available for SCD, and even with optimal care SCD patients still suffer from a myriad of comorbidities to multiple organ systems and have a decreased life span. In this review we will summarize results from trials of HSCT for children or adults with SCD using a variety of graft sources as well as conditioning and GVHD prophylaxis regimens, and discuss the unique challenges that arise in these patients. Recent Findings—AlloHSCT for SCD has been performed on small numbers of patients at multiple centers around the world using several different transplant platforms, and early outcomes are encouraging. Overall survival is excellent, although graft failure remains a challenge.
Author Manuscript
Summary—As alloHSCT becomes safer and more widely available, the procedure should be considered for patients with severe disease phenotypes in whom the potential benefits of transplantation outweigh the complications from the disease. AlloHSCT has been shown to reverse or at least halt the progression of end-organ damage secondary to SCD. More research is needed to understand the mechanisms underlying graft failure in SCD recipients, as well as to understand the biopsychosocial underpinnings of persistent pain in the post-transplant period to maximize the benefit from the transplant procedure. Keywords hematopoietic stem cell transplantation; sickle cell disease; haploidentical donor
Author Manuscript
Introduction Hematopoietic stem cell transplantation (HSCT) was originally developed as a treatment for certain relapsed or refractory hematologic malignancies. In its infancy, allogeneic HSCT was only possible for patients with a fully human leukocyte antigen (HLA)- matched sibling donor. With the development of improved regimens for graft-versus-host disease (GVHD) prophylaxis, the donor pool has expanded to include matched unrelated donors, partially
Address correspondence to Tara M. Robinson, MD, PhD, 1650 Orleans Street, CRB-1 Room 186, Baltimore, MD 21287. The authors declare that they have no conflicts of interest or competing financial or personal relationships that could inappropriately influence the content of this article.
Robinson and Fuchs
Page 2
Author Manuscript
HLA-mismatched related donors, and unrelated umbilical cord blood. Transplant-related mortality is approximately 10% in most recent large studies.[1-5] As the safety of HSCT increases, the risk of undergoing HSCT for non-fatal diseases becomes more acceptable.
Author Manuscript
Sickle cell disease (SCD) is an inherited hemoglobinopathy that causes anemia and other serious morbidities such as retinopathy, nephropathy, acute chest syndrome (ACS), stroke, venous thromboembolism, chronic pain, and acute vaso-occlusive crises (VOC). There are over 100,000 people living with SCD in the United States alone, [6] and many more in Africa and the Middle East. SCD is an attractive target for transplantation given the comorbidities and lack of approved therapies, which currently consist only of red blood cell (RBC) transfusions and hydroxyurea (HU). Even with early identification of patients through newborn screening programs, use of available therapies, and optimal supportive care, SCD patients still have a decreased lifespan.[7] There is also a disproportionately high economic cost to patients with SCD due to disability.[8] AlloHSCT is a potentially curative therapy for SCD because engraftment results in the replacement of recipient blood cells, including RBCs, with those of the unaffected donor. AlloHSCT is reserved only for patients with severe complications of the disease such as stroke, recurrent ACS, or frequent VOC since for patients with a mild phenotype, the benefits of transplantation do not currently outweigh the risks.
HLA-matched sibling transplants
Author Manuscript
Historically, using a fully HLA-matched sibling as a donor for transplantation has been considered the gold standard in terms of safety, engraftment, and GVHD. The first use of HSCT in a SCD patient was actually performed in a child with acute myeloid leukemia. HSCT cured the leukemia but was also curative for SCD since the donor had hemoglobin AS.[9] Since that time other larger scale studies have been performed using myeloablative (MA) conditioning and HLA-matched donors and are summarized in Table 1 and below. Walters published results of the first cohort of 22 patients who underwent transplantation for severe SCD. Two patients died, but 15 of the 20 survivors had successful engraftment and disease-free survival (DFS). End organ function was assessed prospectively, and for the patients who suffered a stroke pre-HSCT, MRI showed stable disease following transplant. In addition, patients with abnormal pulmonary function due to prior ACS had stable lung function following HSCT. This seminal study demonstrated that, although cure of SCD was possible, the high rate of graft failure was a challenge.[10]
Author Manuscript
The Center for International Blood and Marrow Transplant Research retrospectively analyzed 67 pediatric patients who were transplanted between 1989 and 2002. Patients received MA conditioning, mostly with busulfan/cyclophosphamide (Bu/Cy), and GVHD prophylaxis primarily with cyclosporine and methotrexate.[11] Acute GVHD was observed in 10% of patients at 100 days, but chronic GVHD was more common with the five-year probability being 22%. The 5-year probability of DFS was 85%. Graft failure occurred in nine patients and was associated with a history of multiple RBC transfusions pretransplantation. Self-resolving veno-occlusive disease (VOD) developed in four patients, three patients died, and the (OS) survival at five years was 97%.[11]
Curr Opin Hematol. Author manuscript; available in PMC 2017 November 01.
Robinson and Fuchs
Page 3
Author Manuscript
Similar outcomes have been reported by Bernaudin et al. The 87 patients in this study received MA conditioning with Bu/Cy, and anti-thymocyte globulin (ATG) was later added to reduce the risk of graft failure.[12] The majority received grafts from HLA-matched siblings, but four patients had donors with one HLA allele mismatch. Graft failure occurred in seven patients and was associated with transplantation prior to using rabbit ATG for conditioning. There were six transplant-related deaths, with four secondary to severe GVHD. The incidences of acute and chronic GVHD were 20% and 12.6%, respectively. Factors associated with GVHD were age > 15 years and HLA-mismatch. Transplantation was complicated by posterior reversible encephalopathy syndrome (PRES) in seven patients. At long-term follow-up, 77 out of 81 living recipients had full donor chimerism and 79 patients were free of disease.[12]
Author Manuscript Author Manuscript
Long-term follow-up data are available for a cohort of patients who underwent HLAmatched sibling transplantation in Belgium. The first study, published in 1998, reported on 50 subjects who were analyzed in two groups. The first group (n=36) underwent HSCT because of severe comorbidities, and the second group (n=14) had less severe disease but were transplanted because they were returning to their home countries where adequate care for SCD was unavailable. Graft rejection occurred in two cases, although one was salvaged by a second transplant using the same donor. There were six cases of durable mixed hematopoietic chimerism.[16] Patients in this initial study received cyclosporine or cyclosporine plus methotrexate for GVHD prophylaxis. Eighteen patients had seizures in the peri-transplant period, and addition of seizure prophylaxis did not decrease the incidence. [16] The same group published an updated study in 2014 on 50 consecutive patients transplanted between 1988 and 2013, thus including some patients from the original cohort. Rabbit ATG was added to the conditioning after 1991, and starting in 1995 all patients were treated with HU for at least three months prior to HSCT. There were no graft failures, and with a median follow-up of eight years, OS of the entire cohort was 94.1% and event-free survival was 85.6%. [13] The improvement in outcomes was attributed in part to the use of HU. In a small cohort of 24 patients they found that recipients who had received HU prior to HSCT and also received ATG as part of their conditioning regimen (n=13) had no graft failure.[17] They hypothesized that the decrease in CD4+ cells from HU [18] led to decreased graft failure and hence better outcomes.
Author Manuscript
Another case series of 11 patients with SCD who underwent HLA-matched HSCT using MA conditioning and cyclosporine and methotrexate for GVHD prophylaxis was recently published by a group in Spain. Of these 11 patients, one died from acute GVHD of the gut, one had secondary graft failure with reoccurrence of SCD symptoms, and one had stable mixed chimerism.[14] This cohort had a particularly good rate of engraftment, although it’s not exactly clear why their outcomes were better since they used standard conditioning and GVHD prophylaxis regimens. Further analysis of this cohort should be undertaken to determine factors that contributed to high rates of engraftment. There is valid concern in the field regarding both the short- and long-term effects of MA conditioning, and studies are ongoing to determine how to best reduce toxicity. Nonmyeloablative (NMA) conditioning is particularly appealing for adults since their comorbidities from SCD can contribute to being a poor candidate for myeloablation. Several
Curr Opin Hematol. Author manuscript; available in PMC 2017 November 01.
Robinson and Fuchs
Page 4
Author Manuscript
trials investigated the use of less toxic conditioning regimens, and are summarized in Table 2 and below.
Author Manuscript
Krishnamurti and colleagues reported on seven patients who received HLA-matched sibling bone marrow after a reduced-intensity conditioning (RIC) regimen of busulfan, fludarabine, equine ATG, and total lymphoid irradiation, with cyclosporine and mycophenolate mofetil for GVHD prophylaxis. Six of seven patients engrafted, experienced resolution of all disease-related symptoms, and remain stable mixed hematopoietic chimeras following discontinuation of immunosuppression. The seventh patient did not engraft but recovered autologous hematopoiesis.[19] Hsieh et al. developed a NMA protocol and, of 30 SCD patients who received HLA-matched grafts, there was no treatment-related mortality but one patient died from intracranial bleeding after relapse of SCD. An impressive 87% of patients had stable chimerism and no GVHD. Importantly, measures of morbidity such as days in hospital, narcotic use, cardiac function, and anemia were all improved after HSCT.[20] Horan and colleagues tested the hypothesis that adding fludarabine to Bu/Cy and ATG would allow for dose-reduction of busulfan and cyclophosphamide. Cyclophosphamide was reduced by 55% without affecting engraftment, although when they attempted to reduce the busulfan dose two patients did not achieve full donor chimerism, which triggered trialstopping rules. All patients survived and were disease free at follow-up ranging from 9-23 months. There was an increase in GVHD seen in patients who received lower doses of cyclophosphamide, although this represented only four patients, so more study will be needed to understand how the conditioning regimen influences GVHD.[21]
Author Manuscript
Iannone and colleagues published a report on outcomes following NMA transplantation using HLA-identical sibling grafts for six patients with SCD as well as one with thalassemia. The NMA conditioning used fludarabine, total body irradiation, and horse ATG. Only one patient had GVHD, none died, and six of seven had mixed chimerism early post-HSCT. However, as immunosuppression was tapered, all of these patients eventually lost their grafts and recovered with autologous hematopoiesis. Although the trial demonstrated that this NMA approach was safe, the outcome was disappointing and demonstrated the challenges of engraftment in this patient population.[22]
Author Manuscript
The Sickle Cell Unrelated Donor Transplant Trial used RIC and cord blood grafts for pediatric patients with severe SCD. In this trial only three out of eight patients engrafted and remained disease free, while the other five had autologous hematopoietic recovery. There was also one death from extensive chronic GVHD in this cohort.[23] Although the incidence of graft failure in this trial was high, patients did have autologous recovery of blood counts, demonstrating relative safety of the approach and justifying further studies into less toxic conditioning regimens.
Partially HLA-mismatched related donor (HLA-haploidentical) HSCT Although the outcomes of HLA-matched sibling HSCT for SCD are encouraging, it is estimated that only 15% of SCD patients have an unaffected, HLA-matched sibling.[25] In
Curr Opin Hematol. Author manuscript; available in PMC 2017 November 01.
Robinson and Fuchs
Page 5
Author Manuscript
contrast, nearly every patient has an HLA-haploidentical first-degree relative, thus offering a potential solution to the problem of donor availability for patients with SCD.
Author Manuscript
Investigators at St. Jude’s Research Hospital compared long-term outcomes in children receiving transplants from an HLA-matched sibling after MA conditioning versus a haploidentical parent after RIC. GVHD prophylaxis in this study was cyclosporine and methotrexate. At a median follow-up of nine years, 13 of 14 patients receiving an HLAmatched graft were alive, with the one death being attributed to chronic GVHD. At five years all survivors remained engrafted with > 85% donor chimerism. Six of eight patients receiving haploidentical transplant were alive at a median follow-up of seven years, with the two deaths again being attributed to GVHD. However, three of eight haplo recipients experienced graft failure and recurrence of symptoms, leaving only three out of eight patients engrafted and disease-free.[15] All patients in both cohorts who achieved sustained engraftment achieved transfusion independence and decrease in iron load. [15] The Johns Hopkins experience of HSCT for SCD was published in 2012 and included three patients who had an HLA-matched donor and 14 with haploidentical-related donors. The NMA regimen included fludarabine, cyclophosphamide, TBI, and ATG. Patients received high dose post-transplantation cyclophosphamide, mycophenylate mofetil, and either tacrolimus or sirolimus for GVHD prophylaxis. The incidence of graft failure was 43% in haploidentical pairs. However, there was no mortality in this study and only one patient had GVHD of the skin only that did not require treatment. All patients who engrafted became transfusion independent, and of the 17 patients who started the trial, a striking 41% are no longer taking narcotics.[24] The results are encouraging that in the future, transplant can become a more widely utilized and safe option for patients with this chronic disease.
Author Manuscript
Unique challenges in transplantation for sickle cell disease
Author Manuscript
The experience with transplantation in this population has identified several unique challenges as outlined in Table 3. HSCT is known to affect fertility in all patient populations. A study assessed the ovarian reserve of young female SCD patients who had undergone HSCT. Of the nine HSCT patients assessed, all of them had undetectable anti-mullerian hormone and 89% has follicle-stimulating hormone levels in the menopausal range.[26] Similar results were found in the study by Dallas et al., in which only five of nine males and two of four females had normal gonadal function following transplantation.[15] Patients in this study had received MA conditioning, so further study must be done to assess the effect of NMA conditioning on fertility. In a separate prospective trial, over half of female recipients of HSCT had diminished ovarian reserve, and only three of 13 males had normal testosterone levels following HSCT, consistent with a diagnosis of hypogonadotropic hypogonadism.[27] Ovarian hyperstimulation and oocyte preservation has been done successfully in SCD patients prior to undergoing HSCT,[28] and sperm cryopreservation is also possible. It is particularly important for physicians to be proactive about discussing fertility preservation including the use of gamete or embryo cryopreservation since many SCD patients are being transplanted at young ages before they are ready to consider childbearing.
Curr Opin Hematol. Author manuscript; available in PMC 2017 November 01.
Robinson and Fuchs
Page 6
Author Manuscript
The aforementioned studies demonstrate that graft failure is clearly a major challenge in transplantation for SCD. This is in stark contrast to alloHSCT for hematologic malignancies, where graft failure is below 5% in recent studies.[1,3,29,30] Unlike hematologic malignancy patients, SCD patients are not exposed to cytotoxic chemotherapy prior to transplant conditioning and so have intact immune systems that can mediate graft failure. Allosensitization through multiple RBC transfusions also increases the risk of graft failure for patients with SCD. Intensification of the conditioning regimen reduces the risk of graft failure but increases toxicity to vital organs and increases the risk of severe GVHD, an unacceptable complication of alloHSCT for non-malignant disorders. In our opinion, the biggest challenge in alloHSCT for SCD is to develop a conditioning regimen that minimizes toxicity without compromising engraftment.
Author Manuscript
AlloHSCT in the SCD population has a higher incidence of neurological toxicity than patients who are transplanted for other diseases. While the etiology of this is not known, many patients with SCD have pre-existing strokes or silent cerebral infarcts and so may have a low threshold for further damage. In the Belgian study, six out of 50 patients developed PRES. The majority of patients in this trial received cyclosporine and methotrexate for GVHD prophylaxis, with the remainder receiving cyclosporine alone (UCB recipients) or cyclosporine and mycophenolate mofetil. Changing GVHD prophylaxis to sirolimus significantly reduced the incidence of PRES in our cohort.[24] Patients who undergo HSCT for SCD also have a higher incidence of seizures in the peri-transplant period than do other populations. All patients receive anti-convulsants for prophylaxis but this has met with varying degrees of success. Further research is needed to understand the mechanisms behind the neurological complications unique to this population.
Author Manuscript
Conclusions Allogeneic HSCT is a curative option for patients with HSCT. Currently it is only used for patients with severe manifestations of the disease, but as we optimize conditioning regimens and GVHD prophylaxis and safety continually increases, this may become a more widely utilized option. Small numbers of patients have undergone transplants from haploidentical donors, which has been shown to be safe and results are encouraging that in the future this procedure may be available for more patients as the donor pool expands. Graft failure remains the most significant challenge, and more research in preclinical models as well as clinical trials are needed.
References Author Manuscript
1. McCurdy SR, Kanakry JA, Showel MM, Tsai H-L, Bolaños-Meade J, Rosner GL, Kanakry CG, Perica K, Symons HJ, Brodsky RA, et al. Risk-stratified outcomes of nonmyeloablative HLAhaploidentical BMT with high-dose posttransplantation cyclophosphamide. Blood. 2015; 125:3024– 3031. [PubMed: 25814532] 2. Bacigalupo A, Dominietto A, Ghiso A, Di Grazia C, Lamparelli T, Gualandi F, Bregante S, Van Lint MT, Geroldi S, Luchetti S, et al. Unmanipulated haploidentical bone marrow transplantation and post-transplant cyclophosphamide for hematologic malignanices following a myeloablative conditioning: an update. Bone Marrow Transplant. 2015; 50(Suppl 2):S37–9. [PubMed: 26039205]
Curr Opin Hematol. Author manuscript; available in PMC 2017 November 01.
Robinson and Fuchs
Page 7
Author Manuscript Author Manuscript Author Manuscript Author Manuscript
3. Bashey A. Peripheral blood stem cells for T cell-replete nonmyeloablative hematopoietic transplants using post-transplant cyclophosphamide. Biol Blood Marrow Transplant. 2014; 20:598–599. [PubMed: 24641825] 4. Konuma T, Tsukada N, Kanda J, Uchida N, Ohno Y, Miyakoshi S, Kanamori H, Hidaka M, Sakura T, Onizuka M, et al. Comparison of transplant outcomes from matched sibling bone marrow or peripheral blood stem cell and unrelated cord blood in patients 50 years or older. Am J Hematol. 2016; 91:E284–92. [PubMed: 26910296] 5. Valcárcel D, Sierra J, Wang T, Kan F, Gupta V, Hale GA, Marks DI, McCarthy PL, Oudshoorn M, Petersdorf EW, et al. One-antigen mismatched related versus HLA-matched unrelated donor hematopoietic stem cell transplantation in adults with acute leukemia: Center for International Blood and Marrow Transplant Research results in the era of molecular HLA typing. Biol Blood Marrow Transplant. 2011; 17:640–648. [PubMed: 20674756] 6. Hassell KL. Population estimates of sickle cell disease in the U.S. Am J Prev Med. 2010; 38:S512– 21. [PubMed: 20331952] 7. Lanzkron S, Carroll CP, Haywood C. Mortality rates and age at death from sickle cell disease: U.S 1979-2005. Public Health Rep. 2013; 128:110–116. [PubMed: 23450875] 8. Swanson ME, Grosse SD, Kulkarni R. Disability among individuals with sickle cell disease: literature review from a public health perspective. Am J Prev Med. 2011; 41:S390–7. [PubMed: 22099363] 9. Johnson FL, Look AT, Gockerman J, Ruggiero MR, Dalla-Pozza L, Billings FT. Bone-marrow transplantation in a patient with sickle-cell anemia. N Engl J Med. 1984; 311:780–783. [PubMed: 6382010] 10. Walters MC, Patience M, Leisenring W, Eckman JR, Scott JP, Mentzer WC, Davies SC, OheneFrempong K, Bernaudin F, Matthews DC, et al. Bone marrow transplantation for sickle cell disease. N Engl J Med. 1996; 335:369–376. [PubMed: 8663884] 11. Panepinto JA, Walters MC, Carreras J, Marsh J, Bredeson CN, Gale RP, Hale GA, Horan J, Hows JM, Klein JP, et al. Matched-related donor transplantation for sickle cell disease: report from the Center for International Blood and Transplant Research. Br J Haematol. 2007; 137:479–485. [PubMed: 17459050] 12. Bernaudin F, Socié G, Kuentz M, Chevret S, Duval M, Bertrand Y, Vannier J-P, Yakouben K, Thuret I, Bordigoni P, et al. Long-term results of related myeloablative stem-cell transplantation to cure sickle cell disease. Blood. 2007; 110:2749–2756. [PubMed: 17606762] *13. Dedeken L, Lê PQ, Azzi N, Brachet C, Heijmans C, Huybrechts S, Devalck C, Rozen L, Ngalula M, Ferster A. Haematopoietic stem cell transplantation for severe sickle cell disease in childhood: a single centre experience of 50 patients. Br J Haematol. 2014; 165:402–408. [PubMed: 24433465] - Reported outcomes of 50 SCD patients with severe disease manifestations. This study included patients who were treated pre- and post- use of ATG and hydroxyurea, and data demonstrate critical importance of these drugs in contributing to successful HSCT outcomes. 14. García Morin M, Cela E, Garrido C, Bardón Cancho E, Aguado Del Hoyo A, Pascual C, PérezCorral A, Beléndez C. Bone marrow transplant in patients with sickle cell anaemia. Experience in one centre. An Pediatr (Barc). 2016; doi: 10.1016/j.anpedi.2016.03.014 **15. Dallas MH, Triplett B, Shook DR, Hartford C, Srinivasan A, Laver J, Ware R, Leung W. Longterm outcome and evaluation of organ function in pediatric patients undergoing haploidentical and matched related hematopoietic cell transplantation for sickle cell disease. Biol Blood Marrow Transplant. 2013; 19:820–830. [PubMed: 23416852] - Comprehensive assessment of 22 pediatric patients who underwent HSCT for severe SCD. In addition to reporting outcomes of GVHD and survival, this trial included a prospective, very thorough analysis of CNS, renal, cardiac, pulmonary, and 16. Vermylen C, Cornu G, Ferster A, Brichard B, Ninane J, Ferrant A, Zenebergh A, Maes P, Dhooge C, Benoit Y, et al. Haematopoietic stem cell transplantation for sickle cell anaemia: the first 50 patients transplanted in Belgium. Bone Marrow Transplant. 1998; 22:1–6. [PubMed: 9678788] 17. Brachet C, Azzi N, Demulder A, Devalck C, Gourdin A, Gulbis B, Klein A, Le PQ, Loop M, Sariban E, et al. Hydroxyurea treatment for sickle cell disease: impact on haematopoietic stem cell transplantation’s outcome. Bone Marrow Transplant. 2004; 33:799–803. [PubMed: 14767501]
Curr Opin Hematol. Author manuscript; available in PMC 2017 November 01.
Robinson and Fuchs
Page 8
Author Manuscript Author Manuscript Author Manuscript Author Manuscript
*18. Lederman HM, Connolly MA, Kalpatthi R, Ware RE, Wang WC, Luchtman-Jones L, Waclawiw M, Goldsmith JC, Swift A, Casella JF, et al. Immunologic effects of hydroxyurea in sickle cell anemia. Pediatrics. 2014; 134:686–695. [PubMed: 25180279] - This paper demonstrates that hydroxyurea decreases the absolute numbers of total lymphocytes, CD4+ lymphocytes, and CD4 memory cells. This decrease in CD4+ T cells is the proposed mechanism of how administration of HU pre-HSCT contributes to lower rates of GVHD. 19. Krishnamurti L, Kharbanda S, Biernacki MA, Zhang W, Baker KS, Wagner JE, Wu CJ. Stable long-term donor engraftment following reduced-intensity hematopoietic cell transplantation for sickle cell disease. Biol Blood Marrow Transplant. 2008; 14:1270–1278. [PubMed: 18940682] **20. Hsieh MM, Fitzhugh CD, Weitzel RP, Link ME, Coles WA, Zhao X, Rodgers GP, Powell JD, Tisdale JF. Nonmyeloablative HLA-matched sibling allogeneic hematopoietic stem cell transplantation for severe sickle cell phenotype. JAMA. 2014; 312:48–56. [PubMed: 25058217] This trial of 29 patients was one of the first to include older patients, and one of the largest trials of NMA conditioning in this population. It also included prospective analysis of end-organ function, and included secondary endpoints such as use of narcotics post-HSCT and hospitalization rates. 21. Horan JT, Haight A, Dioguardi JL, Brown C, Grizzle A, Shelman C, Kanter J, Hale G, Nieder M, Benton M, et al. Using fludarabine to reduce exposure to alkylating agents in children with sickle cell disease receiving busulfan, cyclophosphamide, and antithymocyte globulin transplant conditioning: results of a dose de-escalation trial. Biol Blood Marrow Transplant. 2015; 21:900– 905. [PubMed: 25617808] 22. Iannone R, Casella JF, Fuchs EJ, Chen AR, Jones RJ, Woolfrey A, Amylon M, Sullivan KM, Storb RF, Walters MC. Results of minimally toxic nonmyeloablative transplantation in patients with sickle cell anemia and beta-thalassemia. Biology of Blood and Marrow Transplantation. 2003; 9:519–528. [PubMed: 12931121] 23. Kamani NR, Walters MC, Carter S, Aquino V, Brochstein JA, Chaudhury S, Eapen M, Freed BM, Grimley M, Levine JE, et al. Unrelated donor cord blood transplantation for children with severe sickle cell disease: results of one cohort from the phase II study from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). Biol Blood Marrow Transplant. 2012; 18:1265– 1272. [PubMed: 22343376] 24. Bolaños-Meade J, Fuchs EJ, Luznik L, Lanzkron SM, Gamper CJ, Jones RJ, Brodsky RA. HLAhaploidentical bone marrow transplantation with posttransplant cyclophosphamide expands the donor pool for patients with sickle cell disease. Blood. 2012; 120:4285–4291. [PubMed: 22955919] 25. Mentzer WC, Heller S, Pearle PR, Hackney E, Vichinsky E. Availability of related donors for bone marrow transplantation in sickle cell anemia. Am J Pediatr Hematol Oncol. 1994; 16:27–29. [PubMed: 8311169] 26. Elchuri SV, Williamson RS, Clark Brown R, Haight AE, Spencer JB, Buchanan I, Hassen-Schilling L, Brown MR, Mertens AC, Meacham LR. The effects of hydroxyurea and bone marrow transplant on Anti-Müllerian hormone (AMH) levels in females with sickle cell anemia. Blood Cells Mol Dis. 2015; 55:56–61. [PubMed: 25976468] 27. Walters MC, Hardy K, Edwards S, Adamkiewicz T, Barkovich J, Bernaudin F, Buchanan GR, Bunin N, Dickerhoff R, Giller R, et al. Pulmonary, gonadal, and central nervous system status after bone marrow transplantation for sickle cell disease. Biol Blood Marrow Transplant. 2010; 16:263– 272. [PubMed: 19822218] 28. Lavery SA, Islam R, Hunt J, Carby A, Anderson RA. The medical and ethical challenges of fertility preservation in teenage girls: a case series of sickle cell anaemia patients prior to bone marrow transplant. Hum Reprod. 2016; doi: 10.1093/humrep/dew084 29. Raiola AM, Dominietto A, Di Grazia C, Lamparelli T, Gualandi F, Ibatici A, Bregante S, Van Lint MT, Varaldo R, Ghiso A, et al. Unmanipulated haploidentical transplants compared with other alternative donors and matched sibling grafts. Biol Blood Marrow Transplant. 2014; 20:1573– 1579. [PubMed: 24910379] 30. Solomon SR, Sanacore M, Zhang X, Brown S, Holland K, Morris LE, Bashey A. Calcineurin inhibitor--free graft-versus-host disease prophylaxis with post-transplantation cyclophosphamide
Curr Opin Hematol. Author manuscript; available in PMC 2017 November 01.
Robinson and Fuchs
Page 9
Author Manuscript
and brief-course sirolimus following reduced-intensity peripheral blood stem cell transplantation. Biol Blood Marrow Transplant. 2014; 20:1828–1834. [PubMed: 25064745]
Author Manuscript Author Manuscript Author Manuscript Curr Opin Hematol. Author manuscript; available in PMC 2017 November 01.
Robinson and Fuchs
Page 10
Author Manuscript
Key Points •
HSCT is a curative option for SCD, and may be an appropriate therapy for patients with severe manifestations of the disease.
•
Graft failure remains the greatest challenge in transplantation for SCD.
•
The use of RIC/NMA conditioning regimens has increased the safety of transplantation, and further research is needed to tailor conditioning regimen to optimize engraftement in this population.
•
The use of haploidentical donors expands the donor pool and is a safe alternative when HLA-matched donor is unavailable.
Author Manuscript Author Manuscript Author Manuscript Curr Opin Hematol. Author manuscript; available in PMC 2017 November 01.
Author Manuscript n=22 3-14 n=67 n=87 2-22 n=50 1-15 n=11 2-13 n=14 5-17
Walters et al[10]
Panepinto et al** [11]
Bernaudin et al [12]
Dedeken et al [13]
García-Morin et al[14]
Dallas et al (MRD cohort) [15]
0%
18% 28%
55%
22%
20%
22.6%/ 3%* 8%
10%
9%
13.4%
18%
Graft failure
21%
0%
20%
12.6%
22%
4.5%
Chronic GVHD
93% at 9 years
90.9% at 3 years
94.1% at 8 years
93.1% at 6 years
97% at 5 years
91% at 4 years
Overall survival
Study included an unknown number of patients reported in Walters et al (1996).
**
Graft failure was 22% in patients who did not receive ATG during conditioning, and 3% in patients who received ATG during conditioning.
*
n, age range (years)
Acute GVHD, Grade II-IV
Author Manuscript
Ref.
Author Manuscript
Summary of MA, HLA-identical HSCT for SCD.
93% at 9 years
81.9% at 3 years
85.6% at 8 years
86.1% at 6 years
85% at 5 years
73% at 4 years
Disease-free survival
Author Manuscript
Table 1 Robinson and Fuchs Page 11
Curr Opin Hematol. Author manuscript; available in PMC 2017 November 01.
Author Manuscript
Author Manuscript
Curr Opin Hematol. Author manuscript; available in PMC 2017 November 01. ~2008-2011, n=8, 7.4-16.2 ~2000-2012, n=8, 4.2-13.4
2006-2011, n=14 (11 haplo and 3 MRD),
Kamani et al [23]
Dallas et al (RIC, haplo cohort) [15]
Bolanos-Meade et al [24]
6 patients with SCD, and 1 patient with thalassemia
**
defined as not requiring treatment for SCD
*
14% primary graft failure, 86% secondary graft failure
1999-2001, n=7**, 3-20
Iannone et al [22]
21.4% overall, 43% for haplo
38%
62.5%
32%
2009-2013, n=14, 4-16
Horan et al [21]
13.3%
14.3%
2004-2013, n=30, 16-65
~1999-2006, n=7, 6-18
Krishnamurti et al[19]
Graft failure
Hsieh et al[20]
Study period, n, age range (years)
Ref.
Unsorted: 80% T: 71% (calculated)
Not reported
NR
Donor chimerism < 10% in long term follow up for all patients
T: 96% (95% CI, 91-101%) (calculated)
M: 67% (95% CI, 55-80%)
T: 48%, (95% CI, 34-62%)
M: 86% (95% CI, 70-100%
T: 68.5% (range 50-90%)
M: 78% (range 76-100%)
Mean donor chimerism, myeloid/T cell compartments
0%
50%
25%
14.3%
14.3%
0%
28.6%
Acute GVHD, II-IV
Author Manuscript
Summary of NMA/RIC and non-HLA-identical HSCT for SCD.
0%
37.5%
12.5%
0%
14.3%
0%
14.3%
Chronic GVHD
100%
75% at 7 years
87.5% at 2 years
100%
100%
96.7% at 3 years
100%
Overall survival
64.7%
38%
37.5%
0%
100%
87%
85.7%
Disease-free survival*
Author Manuscript
Table 2 Robinson and Fuchs Page 12
Robinson and Fuchs
Page 13
Table 3
Author Manuscript
Special considerations for HSCT in SCD populations Challenge
Potential solutions
High incidence of graft failure
Consider HU pre-HSCT, consider early transplant before patients are allo-immunized from multiple transfusions.
High incidence of PRES
Use alternative methods such as sirolimus for GVHD prophylaxis. Use of anticonvulsants is standard but has not proven to be effective.
Incidence of infertility
Fertility preservation including offering gamete retrieval and cryopreservation should be discussed with all patients and their families prior to HSCT.
Chronic pain post-transplant
Consider a multi-disciplinary approach with psychiatry, neurology, and behavioral therapy.
Author Manuscript Author Manuscript Author Manuscript Curr Opin Hematol. Author manuscript; available in PMC 2017 November 01.
Curr Opin Hematol. Author manuscript; available in PMC 2017 November 01. Published in final edited form as: Curr Opin Hematol. 2016 November ; 23(6): 524–529. doi:10.1097/MOH.0000000000000282.
Allogeneic Stem Cell Transplantation for Sickle Cell Disease Tara M. Robinson* and Ephraim J. Fuchs Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
Abstract Author Manuscript
Purpose of Review—As the safety and availability of allogeneic hematopoietic stem cell transplantation (HSCT) have improved, this procedure is becoming a viable option for nonmalignant conditions such as sickle cell disease (SCD). There are very few treatment options available for SCD, and even with optimal care SCD patients still suffer from a myriad of comorbidities to multiple organ systems and have a decreased life span. In this review we will summarize results from trials of HSCT for children or adults with SCD using a variety of graft sources as well as conditioning and GVHD prophylaxis regimens, and discuss the unique challenges that arise in these patients. Recent Findings—AlloHSCT for SCD has been performed on small numbers of patients at multiple centers around the world using several different transplant platforms, and early outcomes are encouraging. Overall survival is excellent, although graft failure remains a challenge.
Author Manuscript
Summary—As alloHSCT becomes safer and more widely available, the procedure should be considered for patients with severe disease phenotypes in whom the potential benefits of transplantation outweigh the complications from the disease. AlloHSCT has been shown to reverse or at least halt the progression of end-organ damage secondary to SCD. More research is needed to understand the mechanisms underlying graft failure in SCD recipients, as well as to understand the biopsychosocial underpinnings of persistent pain in the post-transplant period to maximize the benefit from the transplant procedure. Keywords hematopoietic stem cell transplantation; sickle cell disease; haploidentical donor
Author Manuscript
Introduction Hematopoietic stem cell transplantation (HSCT) was originally developed as a treatment for certain relapsed or refractory hematologic malignancies. In its infancy, allogeneic HSCT was only possible for patients with a fully human leukocyte antigen (HLA)- matched sibling donor. With the development of improved regimens for graft-versus-host disease (GVHD) prophylaxis, the donor pool has expanded to include matched unrelated donors, partially
Address correspondence to Tara M. Robinson, MD, PhD, 1650 Orleans Street, CRB-1 Room 186, Baltimore, MD 21287. The authors declare that they have no conflicts of interest or competing financial or personal relationships that could inappropriately influence the content of this article.
Robinson and Fuchs
Page 2
Author Manuscript
HLA-mismatched related donors, and unrelated umbilical cord blood. Transplant-related mortality is approximately 10% in most recent large studies.[1-5] As the safety of HSCT increases, the risk of undergoing HSCT for non-fatal diseases becomes more acceptable.
Author Manuscript
Sickle cell disease (SCD) is an inherited hemoglobinopathy that causes anemia and other serious morbidities such as retinopathy, nephropathy, acute chest syndrome (ACS), stroke, venous thromboembolism, chronic pain, and acute vaso-occlusive crises (VOC). There are over 100,000 people living with SCD in the United States alone, [6] and many more in Africa and the Middle East. SCD is an attractive target for transplantation given the comorbidities and lack of approved therapies, which currently consist only of red blood cell (RBC) transfusions and hydroxyurea (HU). Even with early identification of patients through newborn screening programs, use of available therapies, and optimal supportive care, SCD patients still have a decreased lifespan.[7] There is also a disproportionately high economic cost to patients with SCD due to disability.[8] AlloHSCT is a potentially curative therapy for SCD because engraftment results in the replacement of recipient blood cells, including RBCs, with those of the unaffected donor. AlloHSCT is reserved only for patients with severe complications of the disease such as stroke, recurrent ACS, or frequent VOC since for patients with a mild phenotype, the benefits of transplantation do not currently outweigh the risks.
HLA-matched sibling transplants
Author Manuscript
Historically, using a fully HLA-matched sibling as a donor for transplantation has been considered the gold standard in terms of safety, engraftment, and GVHD. The first use of HSCT in a SCD patient was actually performed in a child with acute myeloid leukemia. HSCT cured the leukemia but was also curative for SCD since the donor had hemoglobin AS.[9] Since that time other larger scale studies have been performed using myeloablative (MA) conditioning and HLA-matched donors and are summarized in Table 1 and below. Walters published results of the first cohort of 22 patients who underwent transplantation for severe SCD. Two patients died, but 15 of the 20 survivors had successful engraftment and disease-free survival (DFS). End organ function was assessed prospectively, and for the patients who suffered a stroke pre-HSCT, MRI showed stable disease following transplant. In addition, patients with abnormal pulmonary function due to prior ACS had stable lung function following HSCT. This seminal study demonstrated that, although cure of SCD was possible, the high rate of graft failure was a challenge.[10]
Author Manuscript
The Center for International Blood and Marrow Transplant Research retrospectively analyzed 67 pediatric patients who were transplanted between 1989 and 2002. Patients received MA conditioning, mostly with busulfan/cyclophosphamide (Bu/Cy), and GVHD prophylaxis primarily with cyclosporine and methotrexate.[11] Acute GVHD was observed in 10% of patients at 100 days, but chronic GVHD was more common with the five-year probability being 22%. The 5-year probability of DFS was 85%. Graft failure occurred in nine patients and was associated with a history of multiple RBC transfusions pretransplantation. Self-resolving veno-occlusive disease (VOD) developed in four patients, three patients died, and the (OS) survival at five years was 97%.[11]
Curr Opin Hematol. Author manuscript; available in PMC 2017 November 01.
Robinson and Fuchs
Page 3
Author Manuscript
Similar outcomes have been reported by Bernaudin et al. The 87 patients in this study received MA conditioning with Bu/Cy, and anti-thymocyte globulin (ATG) was later added to reduce the risk of graft failure.[12] The majority received grafts from HLA-matched siblings, but four patients had donors with one HLA allele mismatch. Graft failure occurred in seven patients and was associated with transplantation prior to using rabbit ATG for conditioning. There were six transplant-related deaths, with four secondary to severe GVHD. The incidences of acute and chronic GVHD were 20% and 12.6%, respectively. Factors associated with GVHD were age > 15 years and HLA-mismatch. Transplantation was complicated by posterior reversible encephalopathy syndrome (PRES) in seven patients. At long-term follow-up, 77 out of 81 living recipients had full donor chimerism and 79 patients were free of disease.[12]
Author Manuscript Author Manuscript
Long-term follow-up data are available for a cohort of patients who underwent HLAmatched sibling transplantation in Belgium. The first study, published in 1998, reported on 50 subjects who were analyzed in two groups. The first group (n=36) underwent HSCT because of severe comorbidities, and the second group (n=14) had less severe disease but were transplanted because they were returning to their home countries where adequate care for SCD was unavailable. Graft rejection occurred in two cases, although one was salvaged by a second transplant using the same donor. There were six cases of durable mixed hematopoietic chimerism.[16] Patients in this initial study received cyclosporine or cyclosporine plus methotrexate for GVHD prophylaxis. Eighteen patients had seizures in the peri-transplant period, and addition of seizure prophylaxis did not decrease the incidence. [16] The same group published an updated study in 2014 on 50 consecutive patients transplanted between 1988 and 2013, thus including some patients from the original cohort. Rabbit ATG was added to the conditioning after 1991, and starting in 1995 all patients were treated with HU for at least three months prior to HSCT. There were no graft failures, and with a median follow-up of eight years, OS of the entire cohort was 94.1% and event-free survival was 85.6%. [13] The improvement in outcomes was attributed in part to the use of HU. In a small cohort of 24 patients they found that recipients who had received HU prior to HSCT and also received ATG as part of their conditioning regimen (n=13) had no graft failure.[17] They hypothesized that the decrease in CD4+ cells from HU [18] led to decreased graft failure and hence better outcomes.
Author Manuscript
Another case series of 11 patients with SCD who underwent HLA-matched HSCT using MA conditioning and cyclosporine and methotrexate for GVHD prophylaxis was recently published by a group in Spain. Of these 11 patients, one died from acute GVHD of the gut, one had secondary graft failure with reoccurrence of SCD symptoms, and one had stable mixed chimerism.[14] This cohort had a particularly good rate of engraftment, although it’s not exactly clear why their outcomes were better since they used standard conditioning and GVHD prophylaxis regimens. Further analysis of this cohort should be undertaken to determine factors that contributed to high rates of engraftment. There is valid concern in the field regarding both the short- and long-term effects of MA conditioning, and studies are ongoing to determine how to best reduce toxicity. Nonmyeloablative (NMA) conditioning is particularly appealing for adults since their comorbidities from SCD can contribute to being a poor candidate for myeloablation. Several
Curr Opin Hematol. Author manuscript; available in PMC 2017 November 01.
Robinson and Fuchs
Page 4
Author Manuscript
trials investigated the use of less toxic conditioning regimens, and are summarized in Table 2 and below.
Author Manuscript
Krishnamurti and colleagues reported on seven patients who received HLA-matched sibling bone marrow after a reduced-intensity conditioning (RIC) regimen of busulfan, fludarabine, equine ATG, and total lymphoid irradiation, with cyclosporine and mycophenolate mofetil for GVHD prophylaxis. Six of seven patients engrafted, experienced resolution of all disease-related symptoms, and remain stable mixed hematopoietic chimeras following discontinuation of immunosuppression. The seventh patient did not engraft but recovered autologous hematopoiesis.[19] Hsieh et al. developed a NMA protocol and, of 30 SCD patients who received HLA-matched grafts, there was no treatment-related mortality but one patient died from intracranial bleeding after relapse of SCD. An impressive 87% of patients had stable chimerism and no GVHD. Importantly, measures of morbidity such as days in hospital, narcotic use, cardiac function, and anemia were all improved after HSCT.[20] Horan and colleagues tested the hypothesis that adding fludarabine to Bu/Cy and ATG would allow for dose-reduction of busulfan and cyclophosphamide. Cyclophosphamide was reduced by 55% without affecting engraftment, although when they attempted to reduce the busulfan dose two patients did not achieve full donor chimerism, which triggered trialstopping rules. All patients survived and were disease free at follow-up ranging from 9-23 months. There was an increase in GVHD seen in patients who received lower doses of cyclophosphamide, although this represented only four patients, so more study will be needed to understand how the conditioning regimen influences GVHD.[21]
Author Manuscript
Iannone and colleagues published a report on outcomes following NMA transplantation using HLA-identical sibling grafts for six patients with SCD as well as one with thalassemia. The NMA conditioning used fludarabine, total body irradiation, and horse ATG. Only one patient had GVHD, none died, and six of seven had mixed chimerism early post-HSCT. However, as immunosuppression was tapered, all of these patients eventually lost their grafts and recovered with autologous hematopoiesis. Although the trial demonstrated that this NMA approach was safe, the outcome was disappointing and demonstrated the challenges of engraftment in this patient population.[22]
Author Manuscript
The Sickle Cell Unrelated Donor Transplant Trial used RIC and cord blood grafts for pediatric patients with severe SCD. In this trial only three out of eight patients engrafted and remained disease free, while the other five had autologous hematopoietic recovery. There was also one death from extensive chronic GVHD in this cohort.[23] Although the incidence of graft failure in this trial was high, patients did have autologous recovery of blood counts, demonstrating relative safety of the approach and justifying further studies into less toxic conditioning regimens.
Partially HLA-mismatched related donor (HLA-haploidentical) HSCT Although the outcomes of HLA-matched sibling HSCT for SCD are encouraging, it is estimated that only 15% of SCD patients have an unaffected, HLA-matched sibling.[25] In
Curr Opin Hematol. Author manuscript; available in PMC 2017 November 01.
Robinson and Fuchs
Page 5
Author Manuscript
contrast, nearly every patient has an HLA-haploidentical first-degree relative, thus offering a potential solution to the problem of donor availability for patients with SCD.
Author Manuscript
Investigators at St. Jude’s Research Hospital compared long-term outcomes in children receiving transplants from an HLA-matched sibling after MA conditioning versus a haploidentical parent after RIC. GVHD prophylaxis in this study was cyclosporine and methotrexate. At a median follow-up of nine years, 13 of 14 patients receiving an HLAmatched graft were alive, with the one death being attributed to chronic GVHD. At five years all survivors remained engrafted with > 85% donor chimerism. Six of eight patients receiving haploidentical transplant were alive at a median follow-up of seven years, with the two deaths again being attributed to GVHD. However, three of eight haplo recipients experienced graft failure and recurrence of symptoms, leaving only three out of eight patients engrafted and disease-free.[15] All patients in both cohorts who achieved sustained engraftment achieved transfusion independence and decrease in iron load. [15] The Johns Hopkins experience of HSCT for SCD was published in 2012 and included three patients who had an HLA-matched donor and 14 with haploidentical-related donors. The NMA regimen included fludarabine, cyclophosphamide, TBI, and ATG. Patients received high dose post-transplantation cyclophosphamide, mycophenylate mofetil, and either tacrolimus or sirolimus for GVHD prophylaxis. The incidence of graft failure was 43% in haploidentical pairs. However, there was no mortality in this study and only one patient had GVHD of the skin only that did not require treatment. All patients who engrafted became transfusion independent, and of the 17 patients who started the trial, a striking 41% are no longer taking narcotics.[24] The results are encouraging that in the future, transplant can become a more widely utilized and safe option for patients with this chronic disease.
Author Manuscript
Unique challenges in transplantation for sickle cell disease
Author Manuscript
The experience with transplantation in this population has identified several unique challenges as outlined in Table 3. HSCT is known to affect fertility in all patient populations. A study assessed the ovarian reserve of young female SCD patients who had undergone HSCT. Of the nine HSCT patients assessed, all of them had undetectable anti-mullerian hormone and 89% has follicle-stimulating hormone levels in the menopausal range.[26] Similar results were found in the study by Dallas et al., in which only five of nine males and two of four females had normal gonadal function following transplantation.[15] Patients in this study had received MA conditioning, so further study must be done to assess the effect of NMA conditioning on fertility. In a separate prospective trial, over half of female recipients of HSCT had diminished ovarian reserve, and only three of 13 males had normal testosterone levels following HSCT, consistent with a diagnosis of hypogonadotropic hypogonadism.[27] Ovarian hyperstimulation and oocyte preservation has been done successfully in SCD patients prior to undergoing HSCT,[28] and sperm cryopreservation is also possible. It is particularly important for physicians to be proactive about discussing fertility preservation including the use of gamete or embryo cryopreservation since many SCD patients are being transplanted at young ages before they are ready to consider childbearing.
Curr Opin Hematol. Author manuscript; available in PMC 2017 November 01.
Robinson and Fuchs
Page 6
Author Manuscript
The aforementioned studies demonstrate that graft failure is clearly a major challenge in transplantation for SCD. This is in stark contrast to alloHSCT for hematologic malignancies, where graft failure is below 5% in recent studies.[1,3,29,30] Unlike hematologic malignancy patients, SCD patients are not exposed to cytotoxic chemotherapy prior to transplant conditioning and so have intact immune systems that can mediate graft failure. Allosensitization through multiple RBC transfusions also increases the risk of graft failure for patients with SCD. Intensification of the conditioning regimen reduces the risk of graft failure but increases toxicity to vital organs and increases the risk of severe GVHD, an unacceptable complication of alloHSCT for non-malignant disorders. In our opinion, the biggest challenge in alloHSCT for SCD is to develop a conditioning regimen that minimizes toxicity without compromising engraftment.
Author Manuscript
AlloHSCT in the SCD population has a higher incidence of neurological toxicity than patients who are transplanted for other diseases. While the etiology of this is not known, many patients with SCD have pre-existing strokes or silent cerebral infarcts and so may have a low threshold for further damage. In the Belgian study, six out of 50 patients developed PRES. The majority of patients in this trial received cyclosporine and methotrexate for GVHD prophylaxis, with the remainder receiving cyclosporine alone (UCB recipients) or cyclosporine and mycophenolate mofetil. Changing GVHD prophylaxis to sirolimus significantly reduced the incidence of PRES in our cohort.[24] Patients who undergo HSCT for SCD also have a higher incidence of seizures in the peri-transplant period than do other populations. All patients receive anti-convulsants for prophylaxis but this has met with varying degrees of success. Further research is needed to understand the mechanisms behind the neurological complications unique to this population.
Author Manuscript
Conclusions Allogeneic HSCT is a curative option for patients with HSCT. Currently it is only used for patients with severe manifestations of the disease, but as we optimize conditioning regimens and GVHD prophylaxis and safety continually increases, this may become a more widely utilized option. Small numbers of patients have undergone transplants from haploidentical donors, which has been shown to be safe and results are encouraging that in the future this procedure may be available for more patients as the donor pool expands. Graft failure remains the most significant challenge, and more research in preclinical models as well as clinical trials are needed.
References Author Manuscript
1. McCurdy SR, Kanakry JA, Showel MM, Tsai H-L, Bolaños-Meade J, Rosner GL, Kanakry CG, Perica K, Symons HJ, Brodsky RA, et al. Risk-stratified outcomes of nonmyeloablative HLAhaploidentical BMT with high-dose posttransplantation cyclophosphamide. Blood. 2015; 125:3024– 3031. [PubMed: 25814532] 2. Bacigalupo A, Dominietto A, Ghiso A, Di Grazia C, Lamparelli T, Gualandi F, Bregante S, Van Lint MT, Geroldi S, Luchetti S, et al. Unmanipulated haploidentical bone marrow transplantation and post-transplant cyclophosphamide for hematologic malignanices following a myeloablative conditioning: an update. Bone Marrow Transplant. 2015; 50(Suppl 2):S37–9. [PubMed: 26039205]
Curr Opin Hematol. Author manuscript; available in PMC 2017 November 01.
Robinson and Fuchs
Page 7
Author Manuscript Author Manuscript Author Manuscript Author Manuscript
3. Bashey A. Peripheral blood stem cells for T cell-replete nonmyeloablative hematopoietic transplants using post-transplant cyclophosphamide. Biol Blood Marrow Transplant. 2014; 20:598–599. [PubMed: 24641825] 4. Konuma T, Tsukada N, Kanda J, Uchida N, Ohno Y, Miyakoshi S, Kanamori H, Hidaka M, Sakura T, Onizuka M, et al. Comparison of transplant outcomes from matched sibling bone marrow or peripheral blood stem cell and unrelated cord blood in patients 50 years or older. Am J Hematol. 2016; 91:E284–92. [PubMed: 26910296] 5. Valcárcel D, Sierra J, Wang T, Kan F, Gupta V, Hale GA, Marks DI, McCarthy PL, Oudshoorn M, Petersdorf EW, et al. One-antigen mismatched related versus HLA-matched unrelated donor hematopoietic stem cell transplantation in adults with acute leukemia: Center for International Blood and Marrow Transplant Research results in the era of molecular HLA typing. Biol Blood Marrow Transplant. 2011; 17:640–648. [PubMed: 20674756] 6. Hassell KL. Population estimates of sickle cell disease in the U.S. Am J Prev Med. 2010; 38:S512– 21. [PubMed: 20331952] 7. Lanzkron S, Carroll CP, Haywood C. Mortality rates and age at death from sickle cell disease: U.S 1979-2005. Public Health Rep. 2013; 128:110–116. [PubMed: 23450875] 8. Swanson ME, Grosse SD, Kulkarni R. Disability among individuals with sickle cell disease: literature review from a public health perspective. Am J Prev Med. 2011; 41:S390–7. [PubMed: 22099363] 9. Johnson FL, Look AT, Gockerman J, Ruggiero MR, Dalla-Pozza L, Billings FT. Bone-marrow transplantation in a patient with sickle-cell anemia. N Engl J Med. 1984; 311:780–783. [PubMed: 6382010] 10. Walters MC, Patience M, Leisenring W, Eckman JR, Scott JP, Mentzer WC, Davies SC, OheneFrempong K, Bernaudin F, Matthews DC, et al. Bone marrow transplantation for sickle cell disease. N Engl J Med. 1996; 335:369–376. [PubMed: 8663884] 11. Panepinto JA, Walters MC, Carreras J, Marsh J, Bredeson CN, Gale RP, Hale GA, Horan J, Hows JM, Klein JP, et al. Matched-related donor transplantation for sickle cell disease: report from the Center for International Blood and Transplant Research. Br J Haematol. 2007; 137:479–485. [PubMed: 17459050] 12. Bernaudin F, Socié G, Kuentz M, Chevret S, Duval M, Bertrand Y, Vannier J-P, Yakouben K, Thuret I, Bordigoni P, et al. Long-term results of related myeloablative stem-cell transplantation to cure sickle cell disease. Blood. 2007; 110:2749–2756. [PubMed: 17606762] *13. Dedeken L, Lê PQ, Azzi N, Brachet C, Heijmans C, Huybrechts S, Devalck C, Rozen L, Ngalula M, Ferster A. Haematopoietic stem cell transplantation for severe sickle cell disease in childhood: a single centre experience of 50 patients. Br J Haematol. 2014; 165:402–408. [PubMed: 24433465] - Reported outcomes of 50 SCD patients with severe disease manifestations. This study included patients who were treated pre- and post- use of ATG and hydroxyurea, and data demonstrate critical importance of these drugs in contributing to successful HSCT outcomes. 14. García Morin M, Cela E, Garrido C, Bardón Cancho E, Aguado Del Hoyo A, Pascual C, PérezCorral A, Beléndez C. Bone marrow transplant in patients with sickle cell anaemia. Experience in one centre. An Pediatr (Barc). 2016; doi: 10.1016/j.anpedi.2016.03.014 **15. Dallas MH, Triplett B, Shook DR, Hartford C, Srinivasan A, Laver J, Ware R, Leung W. Longterm outcome and evaluation of organ function in pediatric patients undergoing haploidentical and matched related hematopoietic cell transplantation for sickle cell disease. Biol Blood Marrow Transplant. 2013; 19:820–830. [PubMed: 23416852] - Comprehensive assessment of 22 pediatric patients who underwent HSCT for severe SCD. In addition to reporting outcomes of GVHD and survival, this trial included a prospective, very thorough analysis of CNS, renal, cardiac, pulmonary, and 16. Vermylen C, Cornu G, Ferster A, Brichard B, Ninane J, Ferrant A, Zenebergh A, Maes P, Dhooge C, Benoit Y, et al. Haematopoietic stem cell transplantation for sickle cell anaemia: the first 50 patients transplanted in Belgium. Bone Marrow Transplant. 1998; 22:1–6. [PubMed: 9678788] 17. Brachet C, Azzi N, Demulder A, Devalck C, Gourdin A, Gulbis B, Klein A, Le PQ, Loop M, Sariban E, et al. Hydroxyurea treatment for sickle cell disease: impact on haematopoietic stem cell transplantation’s outcome. Bone Marrow Transplant. 2004; 33:799–803. [PubMed: 14767501]
Curr Opin Hematol. Author manuscript; available in PMC 2017 November 01.
Robinson and Fuchs
Page 8
Author Manuscript Author Manuscript Author Manuscript Author Manuscript
*18. Lederman HM, Connolly MA, Kalpatthi R, Ware RE, Wang WC, Luchtman-Jones L, Waclawiw M, Goldsmith JC, Swift A, Casella JF, et al. Immunologic effects of hydroxyurea in sickle cell anemia. Pediatrics. 2014; 134:686–695. [PubMed: 25180279] - This paper demonstrates that hydroxyurea decreases the absolute numbers of total lymphocytes, CD4+ lymphocytes, and CD4 memory cells. This decrease in CD4+ T cells is the proposed mechanism of how administration of HU pre-HSCT contributes to lower rates of GVHD. 19. Krishnamurti L, Kharbanda S, Biernacki MA, Zhang W, Baker KS, Wagner JE, Wu CJ. Stable long-term donor engraftment following reduced-intensity hematopoietic cell transplantation for sickle cell disease. Biol Blood Marrow Transplant. 2008; 14:1270–1278. [PubMed: 18940682] **20. Hsieh MM, Fitzhugh CD, Weitzel RP, Link ME, Coles WA, Zhao X, Rodgers GP, Powell JD, Tisdale JF. Nonmyeloablative HLA-matched sibling allogeneic hematopoietic stem cell transplantation for severe sickle cell phenotype. JAMA. 2014; 312:48–56. [PubMed: 25058217] This trial of 29 patients was one of the first to include older patients, and one of the largest trials of NMA conditioning in this population. It also included prospective analysis of end-organ function, and included secondary endpoints such as use of narcotics post-HSCT and hospitalization rates. 21. Horan JT, Haight A, Dioguardi JL, Brown C, Grizzle A, Shelman C, Kanter J, Hale G, Nieder M, Benton M, et al. Using fludarabine to reduce exposure to alkylating agents in children with sickle cell disease receiving busulfan, cyclophosphamide, and antithymocyte globulin transplant conditioning: results of a dose de-escalation trial. Biol Blood Marrow Transplant. 2015; 21:900– 905. [PubMed: 25617808] 22. Iannone R, Casella JF, Fuchs EJ, Chen AR, Jones RJ, Woolfrey A, Amylon M, Sullivan KM, Storb RF, Walters MC. Results of minimally toxic nonmyeloablative transplantation in patients with sickle cell anemia and beta-thalassemia. Biology of Blood and Marrow Transplantation. 2003; 9:519–528. [PubMed: 12931121] 23. Kamani NR, Walters MC, Carter S, Aquino V, Brochstein JA, Chaudhury S, Eapen M, Freed BM, Grimley M, Levine JE, et al. Unrelated donor cord blood transplantation for children with severe sickle cell disease: results of one cohort from the phase II study from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). Biol Blood Marrow Transplant. 2012; 18:1265– 1272. [PubMed: 22343376] 24. Bolaños-Meade J, Fuchs EJ, Luznik L, Lanzkron SM, Gamper CJ, Jones RJ, Brodsky RA. HLAhaploidentical bone marrow transplantation with posttransplant cyclophosphamide expands the donor pool for patients with sickle cell disease. Blood. 2012; 120:4285–4291. [PubMed: 22955919] 25. Mentzer WC, Heller S, Pearle PR, Hackney E, Vichinsky E. Availability of related donors for bone marrow transplantation in sickle cell anemia. Am J Pediatr Hematol Oncol. 1994; 16:27–29. [PubMed: 8311169] 26. Elchuri SV, Williamson RS, Clark Brown R, Haight AE, Spencer JB, Buchanan I, Hassen-Schilling L, Brown MR, Mertens AC, Meacham LR. The effects of hydroxyurea and bone marrow transplant on Anti-Müllerian hormone (AMH) levels in females with sickle cell anemia. Blood Cells Mol Dis. 2015; 55:56–61. [PubMed: 25976468] 27. Walters MC, Hardy K, Edwards S, Adamkiewicz T, Barkovich J, Bernaudin F, Buchanan GR, Bunin N, Dickerhoff R, Giller R, et al. Pulmonary, gonadal, and central nervous system status after bone marrow transplantation for sickle cell disease. Biol Blood Marrow Transplant. 2010; 16:263– 272. [PubMed: 19822218] 28. Lavery SA, Islam R, Hunt J, Carby A, Anderson RA. The medical and ethical challenges of fertility preservation in teenage girls: a case series of sickle cell anaemia patients prior to bone marrow transplant. Hum Reprod. 2016; doi: 10.1093/humrep/dew084 29. Raiola AM, Dominietto A, Di Grazia C, Lamparelli T, Gualandi F, Ibatici A, Bregante S, Van Lint MT, Varaldo R, Ghiso A, et al. Unmanipulated haploidentical transplants compared with other alternative donors and matched sibling grafts. Biol Blood Marrow Transplant. 2014; 20:1573– 1579. [PubMed: 24910379] 30. Solomon SR, Sanacore M, Zhang X, Brown S, Holland K, Morris LE, Bashey A. Calcineurin inhibitor--free graft-versus-host disease prophylaxis with post-transplantation cyclophosphamide
Curr Opin Hematol. Author manuscript; available in PMC 2017 November 01.
Robinson and Fuchs
Page 9
Author Manuscript
and brief-course sirolimus following reduced-intensity peripheral blood stem cell transplantation. Biol Blood Marrow Transplant. 2014; 20:1828–1834. [PubMed: 25064745]
Author Manuscript Author Manuscript Author Manuscript Curr Opin Hematol. Author manuscript; available in PMC 2017 November 01.
Robinson and Fuchs
Page 10
Author Manuscript
Key Points •
HSCT is a curative option for SCD, and may be an appropriate therapy for patients with severe manifestations of the disease.
•
Graft failure remains the greatest challenge in transplantation for SCD.
•
The use of RIC/NMA conditioning regimens has increased the safety of transplantation, and further research is needed to tailor conditioning regimen to optimize engraftement in this population.
•
The use of haploidentical donors expands the donor pool and is a safe alternative when HLA-matched donor is unavailable.
Author Manuscript Author Manuscript Author Manuscript Curr Opin Hematol. Author manuscript; available in PMC 2017 November 01.
Author Manuscript n=22 3-14 n=67 n=87 2-22 n=50 1-15 n=11 2-13 n=14 5-17
Walters et al[10]
Panepinto et al** [11]
Bernaudin et al [12]
Dedeken et al [13]
García-Morin et al[14]
Dallas et al (MRD cohort) [15]
0%
18% 28%
55%
22%
20%
22.6%/ 3%* 8%
10%
9%
13.4%
18%
Graft failure
21%
0%
20%
12.6%
22%
4.5%
Chronic GVHD
93% at 9 years
90.9% at 3 years
94.1% at 8 years
93.1% at 6 years
97% at 5 years
91% at 4 years
Overall survival
Study included an unknown number of patients reported in Walters et al (1996).
**
Graft failure was 22% in patients who did not receive ATG during conditioning, and 3% in patients who received ATG during conditioning.
*
n, age range (years)
Acute GVHD, Grade II-IV
Author Manuscript
Ref.
Author Manuscript
Summary of MA, HLA-identical HSCT for SCD.
93% at 9 years
81.9% at 3 years
85.6% at 8 years
86.1% at 6 years
85% at 5 years
73% at 4 years
Disease-free survival
Author Manuscript
Table 1 Robinson and Fuchs Page 11
Curr Opin Hematol. Author manuscript; available in PMC 2017 November 01.
Author Manuscript
Author Manuscript
Curr Opin Hematol. Author manuscript; available in PMC 2017 November 01. ~2008-2011, n=8, 7.4-16.2 ~2000-2012, n=8, 4.2-13.4
2006-2011, n=14 (11 haplo and 3 MRD),
Kamani et al [23]
Dallas et al (RIC, haplo cohort) [15]
Bolanos-Meade et al [24]
6 patients with SCD, and 1 patient with thalassemia
**
defined as not requiring treatment for SCD
*
14% primary graft failure, 86% secondary graft failure
1999-2001, n=7**, 3-20
Iannone et al [22]
21.4% overall, 43% for haplo
38%
62.5%
32%
2009-2013, n=14, 4-16
Horan et al [21]
13.3%
14.3%
2004-2013, n=30, 16-65
~1999-2006, n=7, 6-18
Krishnamurti et al[19]
Graft failure
Hsieh et al[20]
Study period, n, age range (years)
Ref.
Unsorted: 80% T: 71% (calculated)
Not reported
NR
Donor chimerism < 10% in long term follow up for all patients
T: 96% (95% CI, 91-101%) (calculated)
M: 67% (95% CI, 55-80%)
T: 48%, (95% CI, 34-62%)
M: 86% (95% CI, 70-100%
T: 68.5% (range 50-90%)
M: 78% (range 76-100%)
Mean donor chimerism, myeloid/T cell compartments
0%
50%
25%
14.3%
14.3%
0%
28.6%
Acute GVHD, II-IV
Author Manuscript
Summary of NMA/RIC and non-HLA-identical HSCT for SCD.
0%
37.5%
12.5%
0%
14.3%
0%
14.3%
Chronic GVHD
100%
75% at 7 years
87.5% at 2 years
100%
100%
96.7% at 3 years
100%
Overall survival
64.7%
38%
37.5%
0%
100%
87%
85.7%
Disease-free survival*
Author Manuscript
Table 2 Robinson and Fuchs Page 12
Robinson and Fuchs
Page 13
Table 3
Author Manuscript
Special considerations for HSCT in SCD populations Challenge
Potential solutions
High incidence of graft failure
Consider HU pre-HSCT, consider early transplant before patients are allo-immunized from multiple transfusions.
High incidence of PRES
Use alternative methods such as sirolimus for GVHD prophylaxis. Use of anticonvulsants is standard but has not proven to be effective.
Incidence of infertility
Fertility preservation including offering gamete retrieval and cryopreservation should be discussed with all patients and their families prior to HSCT.
Chronic pain post-transplant
Consider a multi-disciplinary approach with psychiatry, neurology, and behavioral therapy.
Author Manuscript Author Manuscript Author Manuscript Curr Opin Hematol. Author manuscript; available in PMC 2017 November 01.
